Combination regimens using 3,3-substituted indoline derivatives

ABSTRACT

This invention relates to cyclic combination therapies and regimens utilizing substituted indoline derivative compounds that are antagonists of the progesterone receptor having the general structure:  
                 
 
     wherein: R 1 , and R 2  are chosen independently from each other from H, OH; OAc; alkylaryl; alkylheteroaryl; 1-propynyl; 3-propynyl; and optionally substituted alkyl, O(alkyl); aryl; or heteroaryl groups; or R 1  and R 2  are joined to form a ring comprising —CH 2 (CH 2 ) n CH 2 — where n=0-5; —CH 2 CH 2 CMe 2 CH 2 CH 2 —; —O(CH 2 ) m CH 2 — where m=1-4; O(CH 2 ) p O— where p=1-4; —CH 2 CH 2 OCH 2 CH 2 —; —CH 2 CH 2 N(H or alkyl)CH 2 CH 2 —;  
     or R 1  and R 2  together comprise a double bond to CMe 2 ; C(cycloalkyl), O, or C(cycloether);  
     R 3  is H, OH, NH 2 , COR A ; or optionally substituted alkenyl or alkynyl groups;  
     R A =H or optionally substituted alkyl, alkoxy, or aminoalkyl groups;  
     R 4 =H, halo, CN, NH 2 , or optionally substituted alkyl, alkoxy, or aminoalkyl;  
     R 5  is selected from optionally substituted benzene ring; a five or six membered heterocyclic ring; a 4 or 7-substituted indole or a substituted benzothiophene; or pharmaceutically acceptable salt thereof. These methods of treatment may be used for contraception or for the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, or mininization of side effects or cyclic menstrual bleeding. Additional uses of the invention include stimulation of food intake.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional of U.S. patent application Ser.No. 09/552,631, filed Apr. 19, 2000, which claims the benefit of thepriority of U.S. patent application Ser. No. 60/183,057, filed May 4,1999, now abandoned.

BACKGROUND OF THE INVENTION

[0002] This invention relates to regimens of administering compounds,which are antagonists of the progesterone receptor in combination with aprogestin, an estrogen, or both.

[0003] Intracellular receptors (IR) form a class of structurally relatedgene regulators known as “ligand dependent transcription factors” (R. M.Evans, Science, 240, 889, 1988). The steroid receptor family is a subsetof the IR family, including progesterone receptor (PR), estrogenreceptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), andmineralocorticoid receptor (MR).

[0004] The natural hormone, or ligand, for the PR is the steroidprogesterone, but synthetic compounds, such as medroxyprogesteroneacetate or levonorgestrel, have been made which also serve as ligands.Once a ligand is present in the fluid surrounding a cell, it passesthrough the membrane via passive diffusion, and binds to the IR tocreate a receptor/ligand complex. This complex binds to specific genepromoters present in the cell's DNA. Once bound to the DNA the complexmodulates the production of nRNA and protein encoded by that gene.

[0005] A compound that binds to an IR and mimics the action of thenatural hormone is termed an agonist, whilst a compound which inhibitsthe effect of the hormone is an antagonist.

[0006] PR antagonists may be used in contraception. In this context theymay be administered alone (Ulmann, et al, Ann. N.Y. Acad. Sci., 261,248, 1995), in combination with a PR agonist (Kekkonen, et al, Fertilityand Sterility, 60, 610, 1993) or in combination with a partial ERantagonist such as tamoxifen (WO 96/19997, published Jul. 4, 1996). PRantagonists may also be useful for the treatment of hormone dependentbreast cancers (Horwitz, et al, Horm. Cancer, 283, pub: Birkhaeuser,Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PRantagonists may also be useful for the treatment of non-malignantchronic conditions such as fibroids (Murphy, et al, J. Clin. Endo.Metab., 76, 513, 1993) and endometriosis (Kettel, et al, Fertility andSterility, 56, 402, 1991). PR antagonists may also be useful in hormonereplacement therapy for post menopausal patients in combination with apartial ER antagonist such as tamoxifen (U.S. Pat. No. 5,719,136). PRantagonists, such as mifepristone and onapristone, have been shown to beeffective in a model of hormone dependent prostate cancer, which mayindicate their utility in the treatment of this condition in men(Michna, et al, Ann. N.Y. Acad. Sci., 761, 224, 1995).

[0007] Jones, et al, (U.S. Pat. No. 5,688,810) describe the PRantagonist dihydroquinoline A.

[0008] Jones, et al, described the enol ether B (U.S. Pat. No.5,693,646) as a PR ligand.

[0009] Jones, et al, described compound C (U.S. Pat. No. 5,696,127) as aPR ligand.

[0010] Zhi, et al, described lactones D, E and F as PR antagonists (J.Med. Chem., 41, 291, 1998).

[0011] Zhi, et al, described the ether G as a PR antagonist (J. Med.Chem., 41, 291, 1998).

[0012] Combs, et al., disclosed the amide H as a ligand for the PR (J.Med. Chem., 38, 4880, 1995).

[0013] Perlman, et. al., described the vitamin D analog I as a PR ligand(Tet. Letters, 35, 2295, 1994).

[0014] Hamann, et al, described the PR antagonist J (Ann. N.Y. Acad.Sci., 761, 383, 1995).

[0015] Chen, et al, described the PR antagonist K (Chen, et al, POI-37,16^(th) Int. Cong. Het. Chem., Montana, 1997).

[0016] Kurihari, et. al., described the PR ligand L (J. Antibiotics, 50,360, 1997).

[0017] Elliott (Smith Kline Beecham) claimed the generic indoline M aspotential endothelin receptor antagonists (WO 94/14434). The patent doesnot claim indolines and lacks the appropriate 5-aryl substitution, i.e.CN and NO₂.

[0018] wherein: R₄=H, Ar, R₁₁, OH, 1-5 C alkoxy (opt. substd. by OH, OMeor halogen), —S(O)_(q)R₁₁, N(R₅)₂, XR₁₁, halogen or NHCOR₆; X=(CH₂)_(n),O, NR₆ or S(O)_(q); n=0-6; q=0-2; R₆=H or 1-4 C alkyl; R₁₁=1-8 C alkyl,2-8 C alkenyl, or 2-8 C alkynyl (all optionally substituted); Ar=(i)optionally substituted phenyl or benzo-fused group of (a) or (b); or(ii) napthyl, indoyl, pyridyl, thienyl, oxazolindyl, oxazolyl,thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl,imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl,morpholinyl, piperidinyl, pyrrolyl or pyrimidyl, all optionallysubstituted by one or more R₁ or R₂ groups.

[0019] U.S. Pat. No. 5,521,166 (Grubb) teaches cyclophasic hormonalregimens comprising an antiprogestin and a progestin wherein theprogestin is administered in the alternating presence and absence of anantiprogestin. The disclosed regimens also provide for use of anestrogen for a period of from 2 to 4 days to prevent breakthroughbleeding.

DESCRIPTION OF THE INVENTION

[0020] This invention provides combination therapies and dosing regimensutilizing antiprogestational agents in combination with one or moreprogestational agents. This invention further provides methods oftreatment and dosing regimens further utilizing in combination withthese antiprogestins and progestins, an estrogen, such as ethinylestradiol.

[0021] These regimens and combinations may be administered to a mammalto induce contraception or for the treatment and/or prevention ofsecondary amenorrhea, dysfunctional bleeding, uterine leiomyomata,endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomasof the endometrium, ovary, breast, colon, and prostate. Additional usesof the invention include stimulation of food intake. The uses herein forthe treatment and/or prevention of the conditions or diseases describedabove includes the continuous administration or periodic discontinuationof administration of the invention to allow for minimization ofeffective dose or minimization of side effects or cyclic menstrualbleeding.

[0022] The use of this invention for contraception includesadministration, preferably orally, to a female of child bearing age anantiprogestin in combination with an estrogen or progestin or both.These administration regimens are preferably carried out over 28consecutive days, with a terminal portion of the cycle containingadministration of no progestins, estrogens or anti-progestins.

[0023] The progestins of these combinations may be administered alone orin combination with an estrogen for the first 14 to 24 days of thecycle, the progestins being administered at a dosage range equal inprogestational activity to about 35 μg to about 150 μg levonorgestrelper day, preferably equal in activity to from about 35 μg to about 100μg levonorgestrel per day. An antiprogestin may then be administeredalone or in combination with an estrogen for a period of 1 to 11 days tobegin on any cycle day between day 14 and 24. The anti-progestin inthese combinations may be administered at a dose of from about 2 μg toabout 50 μg per day and the estrogen may be administered at a dose offrom about 10 μg to about 35 μg per day. In an oral administration, apackage or kit containing 28 tablets will include a placebo tablet onthose days when the antiprogestin or progestin or estrogen is notadministered.

[0024] In a preferred embodiment of this invention, the progestins ofthis invention may be administered alone or in combination with anestrogen for the initial 18 to 21 days of a 28-day cycle, followed byadministration of an antiprogestin, alone or in combination with anestrogen, for from 1 to 7 days.

[0025] The estrogen to be used in the combinations and formulations ofthis invention is preferably ethinyl estradiol.

[0026] Progestational agents useful with this invention include, but arenot limited to, levonorgestrel, norgestrel, desogestrel,3-ketodesogestrel, norethindrone, gestodene, norethindrone acetate,norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest,drospirenone, nomegestrol, or (17-deacetyl)norgestimate. Among thepreferred progestins for use in the combinations of this invention arelevonorgestrel, gestodene and trimegestone.

[0027] Examples of orally administered regimens of this invention over a28 day cycle include administration of a progestational agent solely forthe first 21 days at a daily dose equal in progestational activity tofrom about 35 to about 100 μg of levonorgestrel. An antiprogestincompound of this invention may then be administered at a daily dose offrom about 2 to 50 mg from day 22 to day 24, followed by noadministration or administration of a placebo for days 25 to 28. It ismost preferred that the daily dosages of each relevant active ingredientbe incorporated into a combined, single daily dosage unit, totaling 28daily units per 28-day cycle.

[0028] In another regimen, a progestational agent may be coadministeredfor the first 21 days at a daily dose equal in progestational activityto from about 35 to about 150 μg levonorgestrel, preferably equal inactivity to from about 35 to about 100 μg levonorgestrel, with anestrogen, such as ethinyl estradiol, at a daily dose range of from about10 to about 35 μg. This may be followed as described above with anantiprogestin administered at a daily dose of from about 2 to 50 mg fromday 22 to day 24, followed by no administration or administration of aplacebo for days 25 to 28.

[0029] Still another regimen within the scope of this invention illinclude coadministration from days 1 to 21 of a progestational agent,the progestational agent, preferably levonorgestrel, being administeredat a daily dose equal in progestational activity to from about 35 toabout 100 μg levonorgestrel, and an estrogen, such as ethinyl estradiol,at a daily dose range of from about 10 to about 35 μg. This will befollowed on days 22 to 24 by coadministration of an antiprogestin (2 to50 mg/day) and an estrogen, such as ethinyl estradiol, at a daily doseof from about 10 to about 35 μg. From day 25 to day 28, this regimen maybe followed by no administration or administration of a placebo.

[0030] This invention also provides kits or packages of pharmaceuticalformulations designed for use in the regimens described herein. Thesekits are preferably designed for daily oral administration over a 28-daycycle, preferably for one oral administration per day, and organized soas to indicate a single oral formulation or combination of oralformulations to be taken on each day of the 28-day cycle. Preferablyeach kit will include oral tablets to be taken on each the daysspecified, preferably one oral tablet will contain each of the combineddaily dosages indicated.

[0031] According to the regimens described above, one 28-day kit maycomprise:

[0032] a) an initial phase of from 14 to 21 daily dosage units of aprogestational agent equal in progestational activity to from about 35to about 150 μg levonorgestrel, preferably equal in progestationalactivity to about 35 to about 100 μg levonorgestrel;

[0033] b) a second phase of from 1 to 11 daily dosage units of anantiprogestin compound of this invention, each daily dosage unitcontaining an antiprogestin compound at a daily dosage of from about 2to 50 mg; and

[0034] c) optionally, a third phase of an orally and pharmaceuticallyacceptable placebo for the remaining days of the cycle in which noantiprogestin, progestin or estrogen is administered.

[0035] A preferred embodiment of this kit may comprise:

[0036] a) an initial phase of 21 daily dosage units of a progestationalagent equal in progestational activity to about 35 to about 150 μglevonorgestrel, preferably equal in progestational activity to about 35to about 100 μg levonorgestrel;

[0037] b) a second phase of 3 daily dosage units for days 22 to 24 of anantiprogestin compound of this invention, each daily dosage unitcontaining an antiprogestin compound at a daily dosage of from about 2to 50 mg; and

[0038] c) optionally, a third phase of 4 daily units of an orally andpharmaceutically acceptable placebo for each of days 25 to 28.

[0039] Another 28-day cycle packaging regimen or kit of this inventioncomprises:

[0040] a) a first phase of from 18 to 21 daily dosage units of aprogestational agent equal in progestational activity to about 35 toabout 150 μg levonorgestrel, preferably equal in activity to from about35 to about 100 μg levonorgestrel, and, as an estrogen, ethinylestradiol at a daily dose range of from about 10 to about 35 μg; and

[0041] b) a second phase of from 1 to 7 daily dosage units of anantiprogestin of this invention at a daily dose of from about 2 to 50mg; and

[0042] c) optionally, an orally and pharmaceutically acceptable placebofor each of the remaining 0-9 days in the 28-day cycle in which noprogestational agent, estrogen or antiprogestin is administered.

[0043] A preferred embodiment of the kit described above may comprise:

[0044] a) a first phase of 21 daily dosage units of a progestationalagent equal in progestational activity to about 35 to about 150 μglevonorgestrel, preferably equal in activity to from about 35 to about100 μg levonorgestrel, and, as an estrogen, ethinyl estradiol at a dailydose range of from about 10 to about 35 μg; and

[0045] b) a second phase of 3 daily dosage units for days 22 to 24 of anantiprogestin administered at a daily dose of from about 2 to 50 mg; and

[0046] c) optionally, a third phase of 4 daily dose units of an orallyand pharmaceutically acceptable placebo for each of days 25 to 28.

[0047] A further 28-day packaged regimen or kit of this inventioncomprises:

[0048] a) a first phase of from 18 to 21 daily dosage units, eachcontaining a progestational agent of this invention at a daily doseequal in progestational activity to about 35 to about 150 μglevonorgestrel, preferably equal in activity to from about 35 to about100 μg levonorgestrel, and ethinyl estradiol at a daily dose range offrom about 10 to about 35 μg;

[0049] b) a second phase of from 1 to 7 daily dose units, each dailydose unit containing an antiprogestin of this invention at aconcentration of from 2 to 50 mg; and ethinyl estradiol at aconcentration of from about 10 to about 35 μg; and

[0050] c) optionally, an orally and pharmaceutically acceptable placebofor each of the remaining 0-9 days in the 28-day cycle in which noprogestational agent, estrogen or antiprogestin is administered.

[0051] A preferred embodiment of the package or kit just describedcomprises:

[0052] a) a first phase of 21 daily dosage units, each containing aprogestational agent of this invention at a daily dose equal inprogestational activity to about 35 to about 150 μg levonorgestrel,preferably from about 35 to about 100 μg levonorgestrel, and ethinylestradiol at a daily dose range of from about 10 to about 35 μg;

[0053] b) a second phase of 3 daily dose units for days 22 to 24, eachdose unit containing an antiprogestin of this invention at aconcentration of from 2 to 50 mg; and ethinyl estradiol at aconcentration of from about 10 to about 35 μg; and

[0054] c) optionally, a third phase of 4 daily units of an orally andpharmaceutically acceptable placebo for each of days 25 to 28.

[0055] In each of the regimens and kits just described, it is preferredthat the daily dosage of each pharmaceutically active component of theregimen remain fixed in each particular phase in which it isadministered. It is also understood that the daily dose units describedare to be administered in the order described, with the first phasefollowed in order by the second and third phases. To help facilitatecompliance with each regimen, it is also preferred that the kits containthe placebo described for the final days of the cycle. It is furtherpreferred that each package or kit comprise a pharmaceuticallyacceptable package having indicators for each day of the 28-day cycle,such as a labeled blister package or dial dispenser packages known inthe art.

[0056] In this disclosure, the terms anti-progestational agents,anti-progestins and progesterone receptor antagonists are understood tobe synonymous. Similarly, progestins, progestational agents andprogesterone receptor agonists are understood to refer to compounds ofthe same activity.

[0057] These dosage regimens may be adjusted to provide the optimaltherapeutic response. For example, several divided doses of eachcomponent may be administered daily or the dose may be proportionallyincreased or reduced as indicated by the exigencies of the therapeuticsituation. In the descriptions herein, reference to a daily dosage unitmay also include divided units which are administered over the course ofeach day of the cycle contemplated.

[0058] Compounds of this invention that may be used as theanti-progestational agents in the kits, methods and regimens herein arethose of the Formula I:

[0059] wherein:

[0060] R₁ and R₂ are chosen independently from H, alky, substitutedalkyl; OH; O(alkyl); O(substituted alkyl); OAc; aryl; optionallysubstituted aryl; heteroaryl; optionally substituted heteroaryl;alkylaryl; alkylheteroaryl; 1-propynyl; or 3-propynyl;

[0061] or R₁ and R₂ are joined to form a ring comprising one of thefollowing: —CH₂(CH₂)_(n)CH₂—; —CH₂CH₂CMe₂CH₂CH₂—; —O(CH₂)_(m)CH₂—;O(CH₂)_(p)O—; —CH₂CH₂OCH₂CH₂—; —CH₂CH₂N(H or alkyl)CH₂CH₂—;

[0062] n is an integer from 0 to 5;

[0063] m is an integer from 1 to 4;

[0064] p is an integer from 1 to 4;

[0065] or R₁ and R₂ together comprise a double bond to ═C(CH₃)₂;═C(C₃-C₆ cycloalkyl), ═O or ═C(cycloether), wherein cycloether isselected from tetrahydrofuranyl or hexahydropyranyl;

[0066] R₃ is H, OH, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃to C₆ alkenyl, alkynyl or substituted alkynyl, or COR^(A);

[0067] R^(A) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, C₁ to C₃alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, or substitutedC₁ to C₃ aminoalkyl;

[0068] R₄ is H, halogen, CN, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆aminoalkyl, or substituted C₁ to C₆ aminoalkyl;

[0069] R₅ is selected from the groups a), b) or c):

[0070] a) R₅ is a trisubstituted benzene ring containing thesubstituents X, Y and Z as shown below:

[0071]  X is selected from halogen, OH, CN, C₁ to C₃ alkyl, substitutedC₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃thioalkyl, substituted C₁ to C₃ thioalkyl, S(O)alkyl, S(O)₂alkyl, C₁ toC₃ aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂, C₁ to C₃perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3heteroatoms, COR^(B), OCOR^(B), or NR^(C)COR^(B);

[0072] R^(B) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

[0073] R^(C) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl:

[0074] Y and Z are independent substituents taken from the groupincluding H, halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₃ alkyl, or C₁ toC₃ thioalkyl; or

[0075] b) R₅ is a five or six membered ring with 1, 2, or 3 heteroatomsfrom the group including O, S, SO, S₂ or NR₆ and containing one or twoindependent substituents from the group including H, halogen, CN, NO₂and C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, COR^(D), orNR^(E)COR^(D);

[0076] R^(D) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

[0077] R^(E) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl;

[0078] R₆ is H or C₁ to C₃ alkyl; or

[0079] c) R⁵ is an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety,the moiety being optionally substituted by from 1 to 3 substituentsselected from halogen, lower alkyl, CN, NO₂, lower alkoxy, or CF₃;wherein R₆ and R₇ are independently chosen from H, methyl, ethyl,propyl, butyl, iso-propyl, iso-butyl, cyclohexyl, aryl, substitutedaryl, heteroaryl, or substituted heteroaryl;

[0080] or pharmaceutically acceptable salt thereof

[0081] A preferred set of antiprogestin compounds of this invention isdepicted by structure II:

[0082] wherein:

[0083] R₅ is a disubstituted benzene ring containing the substituents X,and Y as shown below:

[0084] X is selected from halogen, CN, C₁ to C₃ alkoxy, C₁ to C₃ alkyl,NO₂, C₁ to C₃ perfluoroalkyl, 5-membered heterocyclic ring containing 1to 3 heteroatoms, or C₁ to C₃ thioalkoxy;

[0085] Y is a substituent on the 4′ or 5′ position selected from H,halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₄ alkyl, or C₁ to C₃thioalkyl; or

[0086] R₅ is a five membered ring having the structure:

[0087] U is O, S, or NR₆,

[0088] R₆ is H, or C₁ to C₃ alkyl, or C₁ to C₄ CO₂alkyl;

[0089] X′ is selected from halogen, CN, NO₂, C₁ to C₃ alkyl or C₁ to C₃alkoxy;

[0090] Y′ is selected from the group H, F, CN, NO₂ or C₁ to C₄ alkyl; or

[0091] R₅ is a six-membered ring with the structure:

[0092] X¹ is N or CX²;

[0093] X² is halogen, CN or NO₂;

[0094] or pharmaceutically acceptable salt thereof

[0095] The antiprogestin compounds of the formulations and regimens ofthis invention may contain an asymmetric carbon atom and some of thecompounds of this invention may contain one or more asymmetric centersand may thus give rise to optical isomers and diastereomers. While shownwithout respect to stereochemistry in Formula I and II the presentinvention includes such optical isomers and diastereomers; as well asthe racemic and resolved, enantiomerically pure R and S stereoisomers;as well as other mixtures of the R and S stereoisomers andpharmaceutically acceptable salts thereof.

[0096] The term “alkyl” is used herein to refer to both straight- andbranched-chain saturated aliphatic hydrocarbon groups having 1 to 8carbon atoms, preferably 1 to 6 carbon atoms; “alkenyl” is intended toinclude both straight- and branched-chain alkyl group with 1 or 2carbon-carbon double bonds and containing 2 to 8 carbon atoms,preferably 2 to 6 carbon atoms; “alkyl” group is intended to cover bothstraight- and branched-chain alkyl group with at least 1 or 2carbon-carbon triple bonds and containing 2 to 8 carbon atoms,preferably 2 to 6 carbon atoms.

[0097] The terms “substituted alkyl”, “substituted alkenyl”, and“substituted alkynyl” refer to alkyl, alkenyl, and alkynyl as justdescribed having one or more substituents from the group includinghalogen, CN, OH, NO₂, amino, aryl, heterocyclic, substituted aryl,substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy,alkylcarbonyl, alkylcarboxy, alkylamino, arylthio. These substituentsmay be attached to any carbon of alkyl, alkenyl, or alkynyl groupprovided that the attachment constitutes a stable chemical moiety.

[0098] The term “aryl” is used herein to refer to an aromatic systemwhich may be a single ring or multiple aromatic rings fused or linkedtogether as such that at least one part of the fused or linked ringsforms the conjugated aromatic system The aryl groups include but notlimited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, andphenanthryl.

[0099] The term “substituted aryl” refers to an aryl as just definedhaving 1 to 4 substituents from the group including halogen, CN, OH,NO₂, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy,substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, orarylthio.

[0100] The term “heterocyclic” is used herein to describe a stable 4- to7-membered monocyclic or a stable multicyclic heterocyclic ring which issaturated, partially unsaturated, or unsaturated, and which consists ofcarbon atoms and from one to four heteroatoms selected from the groupincluding N, O, and S atoms. The N and S atoms may be oxidized. Theheterocyclic ring also includes any multicyclic ring in which any ofabove defined heterocyclic rings is fused to an aryl ring. Theheterocyclic ring may be attached at any heteroatom or carbon atomprovided the resultant structure is chemically stable. Such heterocyclicgroups include, for example, tetrahydrofuran, piperidinyl, piperazinyl,2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl,indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl,thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl.

[0101] The term “substituted heterocyclic” is used herein to describethe heterocyclic just defined having 1 to 4 substituents selected fromthe group which includes halogen, CN, OH, NO₂, amino, alkyl, substitutedalkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy,aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino,or arylthio. The term “thioalkyl” is used herein to refer to the SRgroup, where R is alkyl or substituted alkyl, containing 1 to 8 carbonatoms. The term “alkoxy” refers to the OR group, where R is alkyl orsubstituted alkyl, containing 1 to 8 carbon atoms. The term “aryloxy”refers to the OR group, where R is aryl or substituted aryl, as definedabove. The term “alkylcarbonyl” refers to the RCO group, where R isalkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1to 6 carbon atoms. The term “alkylcarboxy” indicates the COOR group,where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms,preferably 1 to 6 carbon atoms. The term “aminoalkyl” refers to bothsecondary and tertiary amines wherein the alkyl or substituted alkylgroups, containing 1 to 8 carbon atoms, which may be either the same ordifferent and the point of attachment is on the nitrogen atom The term“halogen” refers to Cl, Br, F, or I.

[0102] The antiprogestational compounds of the present invention can beused in the form of salts derived from pharmaceutically orphysiologically acceptable acids or bases. These salts include, but arenot limited to, the following salts with inorganic acids such ashydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, asthe case may be, such organic acids as acetic acid, oxalic acid,succinic acid, and maleic acid. Other salts include salts with alkalimetals or alkaline earth metals, such as sodium, potassium, calcium ormagnesium in the form of esters, carbamates and other conventional“pro-drug” forms, which, when administered in such form, convert to theactive moiety in vivo.

[0103] When the active compounds of these regimens are employed for theabove utilities, they may be combined with one or more pharmaceuticallyacceptable carriers or excipients, for example, solvents, diluents andthe like, and may be administered orally in such forms as tablets,capsules, dispersible powders, granules, or suspensions containing, forexample, from about 0.05 to 5% of suspending agent, syrups containing,for example, from about 10 to 50% of sugar, and elixirs containing, forexample, from about 20 to 50% ethanol, and the like, or parenterally inthe form of sterile injectable solutions or suspensions containing fromabout 0.05 to 5% suspending agent in an isotonic medium. Suchpharmaceutical preparations may contain, for example, from about 25 toabout 90% of the active ingredient in combination with the carrier, moreusually between about 5% and 60% by weight.

[0104] The pharmacologically active agents of this invention may beadministered orally as well as by intravenous, intramuscular, orsubcutaneous routes. Solid carriers include starch, lactose, dicalciumphosphate, microcrystalline cellulose, sucrose and kaolin, while liquidcarriers include sterile water, polyethylene glycols, non-ionicsurfactants and edible oils such as corn, peanut and sesame oils, as areappropriate to the nature of the active ingredient and the particularform of administration desired. Adjuvants customarily employed in thepreparation of pharmaceutical compositions may be advantageouslyincluded, such as flavoring agents, coloring agents, preserving agents,and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.

[0105] The preferred pharmaceutical compositions from the standpoint ofease of preparation and administration are solid compositions,particularly tablets and hard-filled or liquid-filled capsules. Oraladministration of the compounds is preferred.

[0106] These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid, polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

[0107] The pharmaceutical forms suitable for injectable use includesterile aqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringe ability exits. It must be stable underconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacterial and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), suitable mixtures thereof, and vegetable oil.

[0108] The compounds of this invention can be prepared by the proceduresoutlined in the Schemes illustrated below:

[0109] Typically the antiprogestin compounds of this invention areprepared in a convergent manner as shown is Scheme 1, by a suitablecoupling reaction. For example, a palladium mediated coupling of an arylhalide with an aryl boronic acid provides the desired bi-arylsubstituted target. The choice of the aryl halide-aryl boronic acidcombination is established experimentally.

[0110] As outlined in Scheme 2, the “right side” of the antiprogestincompounds of this invention may be prepared by following the proceduredescribed of Letcher, R. M. et. al., J. Chem. Soc. Perkin Trans., 1993,Vol. 1, pp. 939-944.

[0111] As an example the right side template, 2, is prepared bycondensing an appropriately substituted phenyl hydrazine and a suitableketone to give the corresponding hydrazone. This material is cyclized toan imine in refluxing acetic acid and then reduced to the desiredindoline template 2. Examples 1-7 and 10-20 were prepared by this routeusing the appropriate ketone.

[0112] Alternatively the right side template may be prepared as outlinedin Scheme 3. The commercially available oxindole is di-alkylated at C-3by using an appropriate base and the corresponding alkyl halide to givethe 3,3-dialky-oxindole, 8, or the spiro-cyclic oxindole 9. Theseoxindoles are then brominated under standard conditions and the carbonylgroup is reduced to the desired methylene using a hydride mediatedreduction. The timing of the aryl coupling and the reduction of the2-position carbonyl are established experimentally.

[0113] The right side templates are coupled with an appropriate arylboronic acid using an appropriate palladium (0) catalyst, Scheme 4. Forexample compound 10 is coupled under standard Suzuki conditions with anappropriately substituted aryl-boronic acid to afford compound 11.

[0114] The compounds of this invention, are stable semi-solids and areconveniently converted into their corresponding salts by treatment withacid. Example 1, compound 11 (R₁=R₂=R₃=Me), when treated with HCl indioxane affords the HCl salt (Example 2) as a white solid. The racemicindolines can be separated into their enantiomers by Chiral HPLC, toprovide the individual enantiomers in >98% EE.

[0115] This invention may be further understood by the followingnon-limiting examples.

EXAMPLE 1 2,3,3-Trimethyl-5-(3-Nitro-Phenyl)-2,3-Dihydro-1H-Indole5-Bromo-2,3,3-Trimethyl-2,3-Dihydro-1H-Indole

[0116] This compound was prepared by the procedure of Letcher, R. M. et.al., J. Chem. Soc. Perkin Trans., 1: 939-944, 1993.

[0117] To a solution of 4-bromo-phenyl hydrazine hydrochloride (2.59 g,11.6 mmol) and 3-methyl-2-butanone (1.0 g, 11.6 mmol) in 20 mL benzenewas added acetic acid (catalytic amount) and the resulting solution wasrefluxed with azeotropic removal of H₂O for 14 h. The reaction mixturewas cooled to room temperature and concentrated. The resultingsemi-solid was extracted in acetic acid and refluxed for 12 hours. Thereaction mixture was cooled to room temperature and concentrated. Thesemi-solid residue was extracted in ether and neutralized with K₂CO₃.The ether layer was dried and concentrated. The resulting solid iminewas dissolved in THF-MeOH (6:1), cooled to 0° C. and sodium borohydride(0.5 g, 13.2 mmol) was added. The solution was allowed to warm to roomtemperature and stirred for 0.5 hours. The reaction mixture was pouredinto 15% aqueous HCl and then made basic with K₂CO₃. The organic layerwas separated, washed with brine, dried (Na₂SO₄), and concentrated. Thecrude product was purified by column chromatography (SiO₂, hexane-ethylacetate 9:1). The product was isolated as an orange liquid (2.1 g, 75%):¹H-NMR (CDCl₃) δ1.03 (s, 3H), 1.15 (d, J=6.6 Hz, 3H), 1.25 (s, 3H), 3.50(q, J=6.6 Hz, 1H), 3.70 (br. s, 1H), 6.45 (d, J=8.7 Hz, 1H), 7.09 (m,2H); ¹³C-NMR (CDCl₃) 15.10, 22.25, 26.11 (q), 43.72 (s), 65.47 (d),110.32 (s), 110.70, 125.47, 129.75 (d), 141.48, 148.33 (s); MS (EI) m/z240, 242 (M+H)⁺.

[0118] A solution of 5-bromo-2,3,3-trimethyl-2,3-dihydro-1H-indole (0.5g, 2.1 mmol) and tetrakis-(triphenylphosphine) palladium (0.14 g, 0.12mmol) in dimethoxyethane (10 mL) was cycled under N₂-vacuum (4×) andthen stirred under N₂ for 0.5 hours. To this mixture was then added3-nitrophenylboronic acid (0.42 g, 2.5 mmol) followed by a solution ofNa₂CO₃ (0.36 g, 3.4 mmol) in 5 mL water cycled under N₂-vacuum (3×). Thesolution was brought to reflux for 6 hours then cooled to roomtemperature, poured into water and extracted with EtOAc. The combinedorganic extracts were washed with water, brine, dried (Na₂SO₄), andevaporated. The residue was purified by column chromatography (SiO₂,methylenechloride:hexane 1:3) to afford the title compound (0.48 g, 82%)as an orange semi-solid: ¹H NMR (CDCl₃) δ1.12 (s, 3H), 1.21 (d, J=6.6Hz, 3H), 1.35 (s, 3H), 3.60 (q, J=6.6 Hz, 1H), 3.9 (br s, 1H), 6.69 (d,J=7.9 Hz, 1H), 7.28-7.29 (m, 2H), 7.32 (d, J=1.9 Hz, 1H), 7.53 (dd,J=7.9, 7.9 Hz, 1H), 7.85 (ddd, J=7.9, 2.0, 2.0 Hz, 1H), 8.07 (ddd,J=7.9, 2.0, 2.0 Hz, 1H), 8.08 (d, J=7.9 Hz, 1H), 8.39 (dd, J=2.0, 2.0Hz, 1H); ¹³C-NMR (CDCl₃) δ15.27, 22.54, 26.39 (q), 43.53 (s), 65.57 (d),109.48, 120.67, 121.04, 121.10, 126.58 (d), 129.15 (s), 129.53, 132.35(d), 140.18, 143.64, 148.78, 150.11 (s); MS (EI) m/z 283 (M+H)⁺.

EXAMPLE 2 2,3,3-Trimethyl-5-(3-Nitro-Phenyl)-2,3-Dihydro-1H-IndoleHydrochloride

[0119] A solution of2,3,3-trimethyl-5-(3-nitro-phenyl)-2,3-dihydro-1H-indole (0.8 g, 2.79mmol) in 20 mL of 1:1 ether:dioxane at room temperature was treated with1.5 mL of a 4 M HCl/dioxane solution. The resulting solid was isolatedby filtration and washed with hexane to afford the title compound (0.81g, 90%) as a tan solid: m.p. 240-241° C.; ¹H-NMR (CDCl₃) δ1.37 (s, 3H),1.51 (s, 3H), 4.01 (d, J=6.5 Hz, 1H), 7.51 (s, 1H), 7.59 (d, J=7.3 Hz,1H), 7.7 (dd, J=7.9, 7.9 Hz, 1H), 7.8 (d, J=7.9, Hz, 1H), 7.89 (d, J=7.7Hz, 1H), 8.3 (dd, J=7.9, 1.8 Hz, 1H), 8.42 (s, 1H), 11.9 (br s, 2H); MS(EI) m/z 283 (M+H)⁺.

EXAMPLE 3 (2-R ORS)-2,3,3-Trimethyl-5-(3-Nitro-Phenyl)-2,3-Dihydro-1H-Indole And EXAMPLE4 (2-S OR R)-2,3,3-Trimethyl-5-(3-Nitro-Phenyl)-2,3-Dihydro-1H-Indole

[0120] A sample of racemic2,3,3-trimethyl-5-(3-nitro-phenyl)-2,3-dihydro-1H-indole (25 mg), asprepared in example 2, was separated by a chiral preparative HPLC[column: Chiralcel OD, 4.6×250 mm, isocratic, 5:95 IPA:hexane, flowrate=1 mL/min; injection volume=5 μL; retention times: 3, 9.2 min and 4,10.39 min.] to provide the enantiomers 3 and 4 as orange semi-solids.Chiral Analytical HPLC determined that the enantiomers had >99% EE.Examples 3 and 4 have spectral data identical to the racemic material,example 1: ¹H-NMR (CDCl₃) δ1.12 (s, 3H), 1.21 (d, J=6.6 Hz, 3H), 1.35(s, 3H), 3.60 (q, J=6.6 Hz, 1H), 3.9 (br s, 1H), 6.69 (d, J=7.9 Hz, 1H),7.28-7.29 (m, 2H), 7.32 (d, J=1.9 Hz, 1H), 7.53 (dd, J=7.9, 7.9 Hz, 1H),7.85 (ddd, J=7.9, 2.0, 2.0 Hz, 1H), 8.07 (ddd, J=7.9, 2.0, 2.0 Hz, 1H),8.08 (d, J=7.9 Hz, 1H), 8.39 (dd, J=2.0, 2.0 Hz, 1H); MS (EI) m/z 283(M+H)⁺.

EXAMPLE 52,3,3-Diethyl-2-Methyl-5-(3-Nitro-Phenyl)-2,3-DIHYDRO-1H-Indole5-Bromo-3,3-Diethyl-2-Methyl-2,3-Dihydro-1H-Indole

[0121] This compound was prepared according to the procedure for Example1 using 4-bromo-phenyl hydrazine hydrochloride (5.9 g, 26.3 mmol) and3-ethyl-2-pentanone (3.0 g, 26.3 mmol). The subtitled compound (4.5 g)was obtained in 65% yield as a yellowish oil: ¹H-NMR (CDCl₃) δ0.81(t,J=7.4 Hz, 3H), 0.83 (t, J=7.4 Hz, 3H), 1.18 (d, J=6.5 Hz, 3H), 1.42 (dq,J=14.0, 7.4 Hz, 1H), 1.66 (dq, J=14.0, 7.4 Hz, 3H), 3.73 (q, J=6.5 Hz,1H), 6.47 (d, J=8.2 Hz, 1H), 7.02 (d, J=2 Hz, 1H), 7.09 (dd, J=8.2, 2.0Hz, 1H); ¹³C-NMR (CDCl₃) δ10.46, 10.66, 17.70 (q), 26.5, 29.67 (t),52.25 (s), 64.80 (d), 111.64 (s), 112.41, 129.07, 131.58 (d), 139.57,151.04 (s); MS (EI) m/z 268, 270 (M+H)⁺.

[0122] Using the standard coupling conditions given in Example 1 thetitle compound was prepared from5-bromo-3,3-diethyl-2-methyl-2,3-dihydro-1H-indole (0.13 g, 0.45 mmol),tetrakis-(triphenylphosphine) palladium (0.05 g, 0.04 mmol) indimethoxyethane (4 mL) with 3-nitrophenylboronic acid (0.09 g, 0.54mmol) and sodium carbonate (0.15 g, 4.95 mmol) in 2 mL of water. Thetitle compound (0.09 g, 65%) was obtained as a red brown glass: ¹H NMR(CDCl₃) δ0.86 (dt, J=4.0, 4.0 Hz, 3H), 0.88 (dt, J=4.0, 4.0 Hz, 3H),1.24 (d, J=6.6 Hz, 3H), 1.5 (dq, J=14.1, 7.3 Hz, 1H), 1.66-1.84 (m, 3H),3.81 (q, J=6.6 Hz, 1H), 6.69 (d, J=8.0 Hz, 1H), 7.20 (d, J=1.9 Hz, 1H),7.32 (dd, J=8.0, 1.9 Hz, 1H), 7.53 (dd, J=8.0, 8.0 Hz, 1H), 7.85 (dd,J=7.9, 1.1 Hz, 1H), 8.09 (dd, J=7.9, 1.1 Hz, 1H), 8.4 (dd, J=1.9 Hz,1H); ¹³C-NMR (CDCl₃) δ8.99, 9.14, 16.24 (q), 24.87, 28.14 (t), 50.30(s), 63.31 (d), 109.56, 120.80, 121.22, 123.19, 126.76 (d), 128.64 (s),129.67, 132.55 (d), 136.5, 143.92, 148.95, 151.07 (s); MS (EI) m/z 310(M)⁺.

EXAMPLE 64A-Methyl-6-(3-Nitro-Phenyl)-2,3,4,4A,9,9A-Hexahydro-1H-Carbazole6-BROMO-4A-METHYL-2,3,4,4A,9,9A-HEXAHYDRO-1H-CARBAZOLE

[0123] This compound was prepared by the procedure of Example 1 using4-bromo-phenyl hydrazine hydrochloride (2.0 g, 8.95 mmol) and2-methylcyclohexanone (1.0 g, 8.95 mmol). The subtitled compound (1.5 g,65%) was obtained as a yellow oil: ¹H NMR (CDCl₃) δ1.26 (s, 3H),1.38-1.46 (m, 4H), 1.56-1.68 (mn, 4H), 3.4 (t, J=4.4 Hz, 1H), 3.6 (br s,1H), 6.53 (d, J=8 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 7.09 (dd, J=8.0, 2.0Hz, 1H); ¹³C-NMR (CDCl₃) δ21.45, 21.87 (t), 23.96 (q), 27.92, 35.32 (t),43.56 (s), 66.65 (d), 110.73 (s), 111.88, 125.25, 129.99 (d), 142.17,149.03 (s); MS (EI) m/z 268, 270 (M+H)⁺.

[0124] Using the standard coupling conditions given in Example 1, thetitle compound was prepared using6-bromo-4a-methyl-2,3,4,4a,9,9a-hexahydro-1H-carbazole (1.6 g, 6.0mmol), tetrakis(triphenylphosphine) palladium (0.4 g, 0.35 mmol) indimethoxyethane (30 mL) with 3-nitrophenylboronic acid (1.2 g, 7.2 mmol)and sodium carbonate (1.9 g, 18 mmol) in 10 mL water. The pure product(1.2 g, 70%) was obtained as an orange foam: ¹H NMR (CDCl₃) δ1.36 (s,3H), 1.44-1.74 (m 8H), 3.49 (t, J=4.4 Hz, 1H), 3.83 (br s, 1H), 6.75 (d,J=8.0 Hz, 1H), 7.26 (d, J=1.9 Hz, 1H), 7.32 (dd, J=8.0, 1.9 Hz, 1H),7.53 (dd, J=8.0, 8.0 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 8.08 (dd, J=8.0,2.0 Hz, 1H), 8.39 (dd, J=2.0, 2.0 Hz, 1H); ¹³C-NMR (CDCl₃) δ21.27, 21.71(t), 23.87 (q), 27.76, 35.29 (t), 43.06 (s), 66.46 (d), 110.41, 120.57,120.83, 121.24, 126.55 (d), 129.26 (s), 129.68, 132.55 (d), 140.66,143.86, 148.95, 150.51 (s); MS (EI) m/z 309 (M+H)⁺.

EXAMPLE 71,2-Dihydro-2-Methyl-5-(3-Nitro-Phenyl)Spiro[Cyclohexane-1,3-[3H]Indole]5-Bromo-1,2-Dihydro-2-Methylspiro[Cyclohexane-1,3-[3H]Indole]

[0125] Using the conditions given in Example 1 the subtitled compoundwas prepared from 4-bromo-phenyl hydrazine HCl (3.5 g, 15.7 mmol) andcyclohexyl methyl ketone (2.0 g, 15.7 mmol). The pure material (3.0 g,68%) was obtained as an oil: ¹H NMR (CDCl₃) δ1.09 (d, J=6.5 Hz, 3H),1.25-1.73 (m, 10H), 3.45 (br s, 1H), 3.71 (q, J=6.5 Hz, 1H), 6.47 (d,J=8.2 Hz, 1H), 7.09, dd, J=8.2, 2.0 Hz, 1H), 7.19 (d, J=2.0 Hz, 1H);¹³C-NMR (CDCl₃) δ17.22 (q), 23.19, 23.44, 26.16, 30.17, 36.70 (t), 47.99(s), 62.34 (d), 110.08 (s), 111.07, 126.83, 130.08 (d), 139.98, 148.49(s); MS (EI) m/z 280, 282 (M+H)⁺.

[0126] Using the standard coupling conditions given in Example 1 thetitle compound was prepared from5-bromo-1,2-dihydro-2-methylspiro[cyclohexane-1,3-[3H] indole] (0.5 g,1.65 mmol), tetrakis(triphenylphosphine) palladium (0.08 g, 0.07 mmol)in dimethoxy-ethane (5 mL) with 3-nitrophenylboronic acid (0.33 g, 1.98mmol) and sodium carbonate (0.53 g, 4.95 mmol) in 5 mL water. The purematerial (0.35 g, 55%) was obtained as an orange brown semi-solid: ¹HNMR (CDCl₃) δ1.16 (d, J=6.4 Hz, 3H), 1.38-1.83 (m, 10H), 3.7 (br s, 1H),3.8 (q, J=6.4 Hz, 1H), 6.69 (d, J=8.0 Hz, 1H), 7.31 (dd, J=8.0, 1.8 Hz,1H), 7.53 (dd, J=8.0, 8.0 Hz, 1H), 7.86 (d, J=7.3 Hz, 1H), 8.09 (d,J=8.0 Hz, 1H), 8.39 (dd, J=1.9, 1.9 Hz, 1H); ¹³C-NMR (CDCl₃) δ17.45 (q),23.32, 23.70, 26.21, 30.31, 37.07 (t), 47.77 (s), 62.11 (d), 109.81,120.78, 121.23, 122.40, 126.92 (d), 128.96 (s), 129.66, 132.51 (d),138.63, 143.92, 148.94, 150.1 (s); MS (EI) m/z 322 (M)⁺.

EXAMPLE 8 3,3-Dimethyl-5-(3-Nitro-Phenyl)-2,3-Dihydro-1H-Indole(Way-160655) 3,3-Dimethyl-1,3-Dihydro-2H-Indol-2-One

[0127] This compound was prepared using the general method described byA. Kende, Synth. Commun., 1: 12 (1982). The crude material was purifiedby column chromatography (SiO₂, methylenechloride:hexane 1:3) to affordthe subtitled compound which was consistent with the reported spectraldata.

[0128] The above oxindole (0.65 g, 4.03 mmol) and sodium acetate (0.334g, 4.07 mmol) were stirred in acetic acid (5.0 mL). Bromine (0.66 g,0.00413 mol) in acetic acid (5.0 mL) was added drop-wise to the reactionmixture. The reaction was stirred for 50 minutes, and then poured intowater (10 mL). The mixture was made basic with sodium carbonate,extracted with ethyl acetate, dried (MgSO₄), filtered, and evaporated togive 5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.89 g, 92%): ¹HNMR (DMSO-d₆) 1.21 (s, 6H), 6.76 (d, J=8.22 Hz, 1H), 7.29 (dd, J=2.1,8.2 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 10.4 (s, 1H).

[0129] To a solution of the5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.9 g, 3.7 mmol) in 20mL THF at 0° C. was added a borane-methylsulfide complex (2M in THF, 38mL, 75 mmol). The reaction mixture was warmed to room temperature thenbrought to reflux for 4 hours. The mixture was cooled to roomtemperature and poured into H₂O/CH₂Cl₂ and washed with 5% NaHCO₃. Theorganic layer was washed with brine, dried (Na₂SO₄) and concentrated.The crude product was extracted in MeOH, trimethylamine N-oxide (2.0 g,26.6 mmol) was added, and the solution was brought to reflux for 2hours. The reaction mixture was cooled, concentrated and the cruderesidue purified by column chromatography (SiO₂, methylene chloride) toafford 5-bromo-3,3-dimethyl-2,3-dihydro-1H-indole (0.074 g, 87%) as ayellow oil: ¹H NMR (CDCl₃) δ1.29 (s, 6H), 3.30 (s, 2H), 3.5 (br s, 1H),6.49 (d, J=8.8 Hz, 1H), 7.08-7.12 (m, 2H); ¹³C-NMR (CDCl₃) δ27.69 (q),42.21 (s), 62.01 (d), 110.38 (s), 111.09, 125.46, 130.09 (d), 141.03,149.52 (s); MS (EI) m/z 225, 227 (M)⁺.

[0130] Using the standard coupling conditions given in Example 1, thetitle compound was prepared from5-bromo-3,3-dimethyl-2,3-dihydro-1H-indole (0.25 g, 1.1 mmol),tetrakis(triphenylphosphine) palladium (0.08 g, 0.07 mmol) indimethoxyethane (5 mL) with 3-nitrophenylboronic acid (0.22 g, 1.3 mmol)and sodium carbonate (0.35 g, 3.3 mmol) in 5 mL water. The titlecompound (0.17 g, 60%) was obtained as a brown semi-solid: ¹H NMR(CDCl₃) δ1.38 (s, 3H), 3.40 (s, 2H), 6.72 (d, J=8.0 Hz, 1H), 7.29-7.34(m, 2H), 7.54 (dd, J=8.0, 8.0 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 8.09 (dd,J=8.0, 1.5 Hz, 1H), 8.40 (dd, J=2.0, 2.0 Hz, 1H); ¹³C-NMR (CDCl₃) δ27.89(q), 41.93 (s), 62.05 (d), 109.78, 120.87, 121.02, 121.23, 126.87 (d),129.19 (s), 129.69, 132.52 (d), 139.64, 143.75, 148.94, 151.17 (s); MS(EI) m/z 268 (M)⁺.

EXAMPLE 95′-(3-Chlorophenyl)-1′,2′-Dihydrospiro[Cyclohexane-1,3′-[3H]Indole]Spiro [Cyclohexane-1,3′-[3H]Indol]-2′-(1′H) One

[0131] A solution of the oxindole (25 g, 190 mmol) in 800 mL ofanhydrous THF was cooled to −20° C., n-butyllithium (2.5M in hexanes,152 mL, 0.38 mol) slowly added, followed by the addition ofN,N,N′,N′-tetramethylenediamine (51 mL, 0.38 mol). After 15 minutes,1,5-diiodopentane (174 g, 0.54 mol) was added slowly and the mixture wasallowed to warm to room temperature. After stirring for 16 hourssaturated aqueous ammonium chloride solution (1L) and ethylacetate (1L)were added. After 15 minutes, the layers were separated and the aqueousphase was extracted with ethyl acetate. The combined organic layers wereextracted with hydrochloric acid (1N, 500 mL), then washed with brine,dried (MgSO₄), and concentrated to obtain an oil. The oil was trituratedwith hexane (200 mL) and benzene (20 mL). The precipitate was collectedand dried in vacuo to provide Spiro[cyclohexane-1,3′-[3H]indol]-2′-(1′H) one (26.3 g, 69.6%) as colorlesscrystals: mp 110-114° C.; ¹H NMR (DMSO-d₆) δ1.67 (m, 10H), 6.84 (d, 1H,J=8 Hz), 6.94 (t, 1H, J=8 Hz), 7.17 (t, 1H, J=8 Hz), 7.44 (d, 1H, J=8Hz), 10.3 (s, 1H).

[0132] To a solution of the above oxindole (17.6 g, 90.0 mmol) in aceticacid (300 mL) was added sodium acetate (8.0 g, 100.0 mmol) and bromine(14.6 g, 91.0 mmol) with stirring. After 30 minutes at room temperature,the reaction mixture was partitioned between water and ethylacetate. Theaqueous phase was extracted with ethylacetate. The combined organiclayers were washed with water, dried (MgSO₄) and evaporated. The residuewas triturated with hexane. The precipitate was collected, and dried invacuo to provide 5-Bromo-spiro[cyclohexane-1,340 -[3H]indol]-2′(1′H)-one(16.5 g, 67%) as off-white crystals: m.p. 196-199° C.; ¹H NMR (DMSO-d₆)δ1.62 (m, 10H), 6.8 (d, 1H, J=6.8 Hz), 7.36 (d, 1H, J=8.2, 1.8 Hz), 7.58(dd, 1H, J=8.2, 1.8 Hz), 10.44 (s, 1H).

[0133] Using the standard coupling conditions given in Example 1, thetitle compound was prepared from the above bromo-oxindole (0.32 g, 1.14mmol) tetrakis(triphenylphosphine) palladium (0.08 g, 0.07 mmol) and3-chlorophenylboronic acid (0.21 g, 1.37 mmol), and sodium carbonate(0.36 g, 3.4 mmol) in water (3 mL).5-(3-chlorophenyl)-spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one (0.28 g,80%) was obtained as a yellow solid: m.p. 164-165° C., ¹H NMR (CDCl₃)δ1.60-1.78 (m, 6H), 1.81-1.99 (m, 4H), 7.04 (d, J=8.1 Hz, 1H), 7.22-7.47(m, 4H), 7.53 (s, 1H), 7.61 (s, 1H), 9.28 (br s, 1H); ¹³C-NMR (CDCl₃)δ20.17, 24.12, 31.92 (t), 47.22 (s), 109.21, 121.94, 124.06, 125.50,125.79, 125.97, 126.38, 128.96 (d), 132.88, 133.59, 135.60, 139.14,142.17, 182.89 (s); MS (EI) m/z 310, 312 (M−H)⁺.

[0134] To a solution of5-(3-chlorophenyl)-spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one (0.42 g,1.4 mmol) in 20 mL THF at 0° C. is added borane-dimethylsulfide complex,(2M in THF, 14 mL, 28 mmol). The reaction mixture was warmed to roomtemperature then brought to reflux for 4 hours. The mixture was cooledto room temperature and poured into H₂O with CH₂Cl₂ and washed with 5%NaHCO₃. The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated. The crude product was extracted in MeOH and trimethylamineN-oxide (1.0 g, 9.0 mmol) was added. The solution was brought to refluxfor 2 hours, the mixture was cooled, concentrated and the crude residuepurified by column chromatography (SiO₂, methylene chloride) to affordthe title compound (0.25 g, 63%) as a yellow oil: ¹H NMR (CDCl₃) δ81.3-1.55 (m, 3H), 1.6-1.85 (m, 7H), 3.1 (br s, 1H), 3.5 (s, 2H), 6,6 (d,J=8.0 Hz, 1H), 7.18-7.32 (m, 4H), 7.4 (dd, J=7.7, 1.5 Hz, 1H), 7.5 (s,1H); ¹³C-NMR (CDCl₃) δ23.65, 26.24, 37.00 (t), 46.58 (s), 57.49 (t),109.95, 121.82, 125.07, 126.36, 126.98, 127.08, 130.29 (d), 130.64,134.91, 139.65, 144.29, 151.09 (s); MS (EI) m/z 298, 300 (M+H)⁺.

EXAMPLE 10 3-(2′,3′,3′-Trimethyl-2′,3-Dihydro-1H-Indol -5′-yl)Benzonitrile

[0135] To a solution of 5-bromo-2,3,3-trimethyl-2,3-dihydro-1H-indole(2.03 g, 8.45 mmol) in dimethoxyethane (50 mL), under nitrogen was addedtetrakis(triphenylphosphine)palladium (0.47 g, 0.4 mmol). After 20minutes at room temperature, 3-formylphenylboronic acid (2.36 g, 16.4mmol) and potassium carbonate (6.80 g, 55 mmol) in water (25 mL) wasadded, and the mixture was heated under reflux. After 2 hours, themixture was cooled, poured into brine and extracted with EtOAc (×2). Thecombined organic extracts were washed with brine, dried (MgSO₄) andevaporated. The residue was then subjected to column chromatography(SiO₂, EtOAc:hexane, 1:8) to afford3-(2,3,3′-trimethyl-2′,3-dihydro-1H-indol-5′-yl) benzaldehyde (0.96 g,3.62 mmol, 43%) as a slightly impure solid that was used without furtherpurification: ¹H NMR (CDCl₃) δ1.11 (s, 3H), 1.22 (d, 3H, J=6.5 Hz), 1.35(s, 3H), 3.59 (dd, 1H, J=13, 7 Hz), 6.69 (d, 1H, J=1 Hz), 7.25 (s, 1H),7.32 (s, 1H), 7.55 (t, 1H, J=7.6 Hz), 7.80 (d, 1H, J=1 Hz), 7.82 (d, 1H,J=1 Hz), 8.05 (s, 1H), 10.07 (s, 1H).

[0136] To a solution of the above compound (0.96 g, 3.62 mmol) inMeCN/H₂O (20 mL, 95:5) was added hydroxylamnine hydrochloride (0.82 g,7.25 mmol). After 1 hour, the mixture was poured into a saturated sodiumhydrogen carbonate solution and extracted with EtOAc (×2). The combinedorganic extracts were washed with water, dried (MgSO₄) and evaporated.The residue was then dissolved in dichloromethane (20 mL) and treatedwith thionyl chloride (0.53 mL, 7.25 mmol). After 16 hours, the mixturewas quenched with saturated sodium hydrogen carbonate solution andconcentrated, partitioned between water and EtOAc, and re-extracted withEtOAc. The combined organic extracts were washed with brine, dried(MgSO₄) and evaporated. Purification by column chromatography(EtOAc:hexane, 1:8) afforded a yellow oil (0.31 g) which was dissolvedin methanol (5 mL) and treated with ethereal hydrogen chloride (1M, 1.3mL, 1.3 mmol) and evaporated. Recrystalization from MeOH/Et₂O thenafforded the title compound (0.20 g, 0.60 mmol, 18%): mp >235° C.(decomp); ¹H NMR (CDCl₃) δ1.57 (s, 3H), 1.36 (d, 3H, J=6.7 Hz), 1.40 (s,3H), 3.72-3.76 (m, 1H), 7.30 (d, 1H, J=8 Hz), 7.67 (t, 2H, J=7 Hz),7.79-7.84 (m, 2H), 8.03 (d, 1H, J=8 Hz), (8.2, s, 1H); MS (EI) m/z 262(M)⁺.

EXAMPLE 11 Pharmacology

[0137] The biological activity for the compounds of the currentinvention was evaluated in the in-vitro assays described below. In-vitropotencies lie in the range 0.01 nM-10,000 nM, and in-vivo potencies inthe range 1 μg/kg to 100 mg/kg.

[0138] The in-vitro biology is determined by (1) competitive radioligandBinding: using the A-form of the human progesterone receptor withprogesterone as the radioligand; (2) co-transfection assay, whichprovides functional activity expressed as agonist EC50 and AntagonistIC50 values; and (3) a T47D cell proliferation, which is a furtherfunctional assay which also provides agonist and antagonist data.

[0139] 1. hPR Binding Assay

[0140] This assay is carried out in accordance with: Pathirana, C.;Stein, R. B.; Berger, T. S.; Fenical, W.; Ianiro, T.; Mais, D. E.;Torres, A.; Glodman, M. E., Nonsteroidal human progesterone receptormodulators from the marine alga cymoplia barbata, J. Steroid BiochemMol. Biol., 1992, 41, 733-738.

[0141] 2. PRE-luciferase Assay in CV-1 Cells

[0142] The object of this assay is to determine a compound'sprogestational or antiprogestational potency based on its effect onPRE-luciferase reporter activity in CV-1 cells co-transfected with humanPR and PRE-luciferase plasmids. The materials methods used in the assayare as follows.

[0143] a. Medium

[0144] The growth medium was as follows: DMEM (BioWhittaker) containing10% (v/v) fetal bovine serum (heat inactivated), 0.1 mM MEMnon-essential amino acids, 100 U/ml penicillin, 100 mg/ml streptomycin,and 2 mM GlutaMax (GIBCO, BRL). The experimental medium was as follows:DMEM (Bio Whittaker), phenol red-free, containing 10% (v/v)charcoal-stripped fetal bovine serum (heat-inactivated), 0.1 mM MEMnon-essential amino acids, 100 U/ml penicillin, 100 mg/ml streptomycin,and 2 mM GlutaMax (GIBCO, BRL).

[0145] b. Cell Culture, Transfection, Treatment, and Luciferase Assay

[0146] Stock CV-1 cells are maintained in growth medium Co-transfectionis done using 1.2×10⁷ cells, 5 mg pLEM plasmid with hPR-B inserted atSphl and BamHl sites, 10 mg pGL3 plasmid with two PREs upstream of theluciferase sequence, and 50 mg sonicated calf thymus DNA as carrier DNAin 250 ml. Electroporation is carried out at 260 V and 1,000 mF in aBiorad Gene Pulser II. After electroporation, cells are resuspended ingrowth medium and plated in 96-well plate at 40,000 cells/well in 200μl. Following overnight incubation, the medium is changed toexperimental medium. Cells are then treated with reference or testcompounds in experimental medium. Compounds are tested forantiprogestational activity in the presence of 3 nM progesterone.Twenty-four hr. after treatment, the medium is discarded, cells arewashed three times with D-PBS (GIBCO, BRL). Fifty μl of cell lysisbuffer (Promega, Madison, Wis.) is added to each well and the plates areshaken for 15 min in a Titer Plate Shaker (Lab Line Instrument, Inc.).Luciferase activity is measured using luciferase reagents from Promega.

[0147] c. Analysis of Results

[0148] Each treatment consists of at least 4 replicates. Log transformeddata are used for analysis of variance and nonlinear dose response curvefitting for both agonist and antagonist modes. Huber weighting is usedto downweight the effects of outliers. EC₅₀ or IC₅₀ values arecalculated from the retransformed values. JMP software (SAS Institute,Inc.) is used for both one-way analysis of variance and non-linearresponse analyses.

[0149] d. Reference Compounds

[0150] Progesterone and trimegestone are reference progestins and RU486is the reference antiprogestin. All reference compounds are run in filldose-response curves and the EC₅₀ or IC₅₀ values are calculated. TABLE 1Estimated EC₅₀, standard error (SE), and 95% confidence intervals (CI)for reference progestins from three individual studies EC50 95% CICompound Exp. (nM) SE lower upper Progesterone 1 0.616  0.026  0.509 0.746  2 0.402  0.019  0.323  0.501  3 0.486  0.028  0.371  0.637 Trimegestone 1 0.0075 0.0002 0.0066 0.0085 2 0.0081 0.0003 0.0070 0.00943 0.0067 0.0003 0.0055 0.0082

[0151] TABLE 2 Estimated IC₅₀, standard error (SE), and 95% confidentinterval (CI) for the antiprogestin, RU486 from three individual studiesIC 50 95% CI Compound Exp. (nM) SE lower upper RU486 1 0.028 0.002 0.0190.042 2 0.037 0.002 0.029 0.048 3 0.019 0.001 0.013 0.027

[0152] Progestational activity: Compounds that increase PRE-luciferaseactivity significantly (p<0.05) compared to vehicle control areconsidered active.

[0153] Antiprogestational activity: Compounds that decrease 3 nMprogesterone induced PRE-luciferase activity significantly (p<0.05)

[0154] EC₅₀: Concentration of a compound that gives half-maximalincrease PRE-luciferase activity (default-nM) with SE.

[0155] IC₅₀: Concentration of a compound that gives half-maximaldecrease in 3 nM progesterone induced PRE luciferase activity (defaultnM) with SE.

[0156] 3. T47D Cell Proliferation Assay

[0157] The objective of this assay is the determination ofprogestational and antiprogestational potency by using a cellproliferation assay in T47D cells. A compound's effect on DNA synthesisin T47D cells is measured. The materials and methods used in this assayare as follows.

[0158] a. Growth Medium

[0159] DMEM:F12 (1:1) (GIBCO, BRL) supplemented with 10% (v/v) fetalbovine serum (not heat-inactivated), 100 U/ml penicillin, 100 mg/mnlstreptonycin, and 2 mM GlutaMax (GIBCO, BRL).

[0160] b. Treatment Medium

[0161] Minimum Essential Medium (MEM) (#51200-038GIBCO, BRL) phenolred-free supplemented with 0.5% charcoal stripped fetal bovine serun,100 U/mnl penicillin, 200 mg/ml streptomycin, and 2 mM GlutaMax (GIBCO,BRL).

[0162] C. Cell Culture

[0163] Stock T47 D cells are maintained in growth medium For BrdUincorporation assay, cells are plated in 96-well plates (Falcon, BectonDickinson Labware) at 10,000 cells/well in growth medium. Afterovernight incubation, the medium is changed to treatment medium andcells are cultured for an additional 24 hr before treatment. Stockcompounds are dissolved in appropriate vehicle (100% ethanol or 50%ethanol/50% DMSO), subsequently diluted in treatment medium and added tothe cells. Progestin and antiprogestin reference compounds are run infull dose-response curves. The final concentration of vehicle is 0.1%.In control wells, cells receive vehicle only. Antiprogestins are testedin the presence of 0.03 nM trimegestone, the reference progestinagonist. Twenty-four hours after treatment, the medium is discarded andcells are labeled with 10 mM BrdU (Amersham Life Science, ArlingtonHeights, Ill.) in treatment medium for 4 hr.

[0164] d. Cell Proliferation Assay

[0165] At the end of BrdU labeling, the medium is removed and BrdUincorporation is measured using a cell proliferation ELISA kit (#RPN250, Amersham Life Science) according to manufacturer's instructions.Briefly, cells are fixed in an ethanol containing fixative for 30 min,followed by incubation in a blocking buffer for 30 min to reducebackground. Peroxidase-labeled anti-BrdU antibody is added to the wellsand incubated for 60 min. The cells are rinsed three times with PBS andincubated with 3,3′5,5′-tetramethylbenzidine (TMB) substrate for 10-20min depending upon the potency of tested compounds. Then 25 μl of 1 Msulfuric acid is added to each well to stop color reaction and opticaldensity is read in a plate reader at 450 nm within 5 min.

[0166] e. Analysis of Results

[0167] Square root-transformed data are used for analysis of varianceand nonlinear dose response curve fitting for both agonist andantagonist modes. Huber weighting is used to downweight the effects ofoutliers. EC₅₀ or IC₅₀ values are calculated from the retransformedvalues. JMP software (SAS Institute, Inc.) is used for both one-wayanalysis of variance and non-linear dose response analyses in bothsingle dose and dose response studies.

[0168] Reference Compounds

[0169] Trimegestone and medroxyprogesterone acetate (MPA) are referenceprogestins and RU486 is the reference antiprogestin. All referencecompounds are run in full dose-response curves and the EC₅₀ or IC₅₀values are calculated. TABLE 3 Estimated EC₅₀, standard error (SE), and95% confidence intervals (CI) for individual studies EC₅₀ 95% CICompound Exp (nM) SE lower upper Trimegestone 1 0.017 0.003 0.007 0.0402 0.014 0.001 0.011 0.017 3 0.019 0.001 0.016 0.024 MPA 1 0.019 0.0010.013 0.027 2 0.017 0.001 0.011 0.024

[0170] TABLE 4 Estimated IC₅₀, standard error, and 95% confidentinterval for the antiprogestin, RU486 IC₅₀ 95% CI Compound Exp (nM) SElower upper RU486 1 0.011 0.001 0.008 0.014 2 0.016 0.001 0.014 0.020 30.018 0.001 0.014 0.022

[0171] EC₅₀: Concentration of a compound that gives half-maximalincrease in BrdU incorporation with SE; IC₅₀: Concentration of acompound that gives half-maximal decrease in 0.1 trimegestone inducedBrdU incorporation with SE.

[0172] All above-noted published references are incorporated herein byreference. Numerous modification and variations of the present inventionare included in the above-identified specification are expected to beobvious to one of skill in the art. Such modifications and alterationsto the methods, solutions, apparatuses of the present invention arebelieved to be encompassed in the scope of the claims appended hereto.

What is claimed:
 1. A method of contraception which comprisesadministering to a female of child bearing age over a period of 28consecutive days: a) a first phase of from 18 to 21 daily dosage unitsof a progestostational agent equal in progestational activity to about35 to about 150 μg levonorgestrel, and ethinyl estradiol at a daily doserange of from about 10 to about 35 μg; and b) a second phase of from 1to 7 daily dosage units of an antiprogestin at a daily dose of fromabout 2 to 50 mg; wherein said antiprogestin is of the formula:

 wherein: R₁ and R₂ are independently selected from the group consistingof H, alkyl, substituted alkyl, OH; O(alkyl), O(substituted alkyl), OAc,aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl,alkylheteroaryl, 1-propynyl, and 3-propynyl; or R₁ and R₂ are joined toform a ring comprising —CH₂(CH₂)_(n)CH₂—; —CH₂CH₂CMe₂CH₂CH₂—;—O(CH₂)_(m)CH₂—; O(CH₂)_(p)O—; —CH₂CH₂OCH₂CH₂—; —CH₂CH₂N(alkyl)CH₂CH₂—,or —CH₂CH₂NHCH₂CH₂—; n is an integer from 0 to 5; m is an integer from 1to 4; p is an integer from 1 to 4; or R₁ and R₂ together comprise adouble bond to ═C(CH₃)₂; ═C(C₃-C₆ cycloalkyl), ═O, or ═C(cycloether),wherein said cycloether is selected from the group consisting oftetrahydrofuranyl and hexahydropyranyl; R₃ is H, OH, NH₂, C₁ to C₆alkyl, substituted C₁ to C₆ alkyl, C₃ to C₆ alkenyl, alkynyl,substituted alkynyl, or COR^(A); R^(A) is H, C₁ to C₃ alkyl, substitutedC₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl; R₄ is H, halogen, CN,NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy,substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, or substituted C₁ toC₆ aminoalkyl; R₅ is selected from the group consisting of (i), (ii),and (iii): (i) a substituted benzene ring of the formula:

X is selected from the group consisting of halogen, OH, CN, C₁ to C₃alkyl, substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ thioalkyl, substituted C₁ to C₃ thioalkyl, S(O)alkyl,S(O)₂alkyl, C₁ to C₃ aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂,C₁ to C₃ perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1to 3 heteroatoms, COR^(B), OCOR^(B), and NR^(C)COR^(B); R^(B) is H, C₁to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ toC₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, orsubstituted C₁ to C₃ aminoalkyl; R^(C) is H, C₁ to C₃ alkyl, orsubstituted C₁ to C₃ alkyl: Y and Z are independently selected from thegroup consisting of H, halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₄alkyl, and C₁ to C₃ thioalkyl; (ii) a five or six membered ring havingit its backbone 1, 2, or 3 heteroatoms selected from the groupconsisting of O, S, SO, SO₂ and NR_(6′) and containing one or twoindependent substituents selected from the group consisting of H,halogen, CN, NO₂ and C₁ to C₄ alkyl, C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, COR^(D), and NR^(E)COR^(D); R^(D) is H, C₁ to C₃ alkyl,substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy,substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, or substituted C₁ toC₃ aminoalkyl; R^(E) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃alkyl; R_(6′) is H, C₁ to C₃ alkyl, or C₁ to C₄ CO₂ alkyl; and c)optionally, an orally and pharmaceutically acceptable placebo for eachremainig day of the 28 consecutive days.
 2. A method of contraception ofclaim 1 which comprises administering to a female of child bearing ageover a period of 28 consecutive days: a) a first phase of 21 dailydosage units of a progestostational agent equal in progestationalactivity to about 35 to about 100 μg levonorgestrel and ethinylestradiol at a daily dose range of from about 10 to about 35 μg; and b)a second phase of 3 daily dosage units of said antiprogestin of formulaI at a daily dose of from about 2 to 50 mg; and c) optionally, a thirdphase of 4 daily dosage units of an orally and pharmaceuticallyacceptable placebo.
 3. A method of contraception which comprisesadministering to a female of child bearing age over a period of 28consecutive days: a) a first phase of from 18 to 21 daily dosage unitscontaining a progestational agent at a daily dose equal inprogestational activity to from about 35 to about 150 μg levonorgestreland ethinyl estradiol at a daily dose range of from about 10 to about 35μg b) a second phase of from 1 to 7 daily dosage units, each dailydosage unit containing an antiprogestin at a concentration of from 2 to50 mg and ethinyl estradiol at a concentration of from about 10 to about35 μg; wherein said antiprogestin is of the formula:

 wherein: R₁ and R₂ are independently selected from the group consistingof H, alkyl, substituted alkyl, OH; O(alkyl), O(substituted alkyl), OAc,aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl,alkylheteroaryl, 1-propynyl, and 3-propynyl; or R₁ and R₂ are joined toform a ring comprising —CH₂(CH₂)_(n)CH₂—; —CH₂CH₂CMe₂CH₂CH₂—;—O(CH₂)_(m)CH₂—; O(CH₂)_(p)O—; —CH₂CH₂OCH₂CH₂—; —CH₂CH₂N(alkyl)CH₂CH₂—,or —CH₂CH₂NHCH₂CH₂—; n is an integer from 0 to 5; m is an integer from 1to 4; p is an integer from 1 to 4; or R₁ and R₂ together comprise adouble bond to ═C(CH₃)₂; ═C(C₃-C₆ cycloalkyl), ═O, or ═C(cycloether),wherein said cycloether is selected from the group consisting oftetrahydrofuranyl and hexahydropyranyl; R₃ is H, OH, NH₂, C₁ to C₆alkyl, substituted C₁ to C₆ alkyl, C₃ to C₆ alkenyl, alkynyl,substituted alkynyl, or COR^(A); R^(A) is H, C₁ to C₃ alkyl, substitutedC₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl; R₄ is H, halogen, CN,NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy,substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, or substituted C₁ toC₆ aminoalkyl; R₅ is selected from the group consisting of (i), (ii),and (iii): (i) a substituted benzene ring of the formula:

X is selected from the group consisting of halogen, OH, CN, C₁ to C₃alkyl, substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ thioalkyl, substituted C₁ to C₃ thioalkyl, S(O)alkyl,S(O)₂alkyl, C₁ to C₃ aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂,C₁ to C₃ perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1to 3 heteroatoms, COR^(B), OCOR^(B), and NR^(C)COR^(B); R^(B) is H, C₁to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ toC₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, orsubstituted C₁ to C₃ aminoalkyl; R^(C) is H, C₁ to C₃ alkyl, orsubstituted C₁ to C₃ alkyl: Y and Z are independently selected from thegroup consisting of H, halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₄alkyl, and C₁ to C₃ thioalkyl; (ii) a five or six membered ring havingit its backbone 1, 2, or 3 heteroatoms selected from the groupconsisting of O, S, SO, SO₂ and NR_(6′) and containing one or twoindependent substituents selected from the group consisting of H,halogen, CN, NO₂ and C₁ to C₄ alkyl, C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, COR^(D), and NR^(E)COR^(D); R^(D) is H, C₁ to C₃ alkyl,substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy,substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, or substituted C₁ toC₃ aminoalkyl; R^(E) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃alkyl; R_(6′) is H, C₁ to C₃ alkyl, or C₁ to C₄ CO₂ alkyl; and c)optionally, a third phase of daily dosage units of an orally andpharmaceutically acceptable placebo, the total of the daily dosage unitsbeing
 28. 4. A method of contraception of claim 3 which comprisesadministering to a female of child bearing age over a period of 28consecutive days: a) a first phase of 21 daily dosage units, each dailydosage unit containing a progestational agent at a daily dose equal inprogestational activity to about 35 to about 100 μg levonorgestrel andethinyl estradiol at a daily dose range of from about 10 to about 35 μgb) a second phase of 3 daily dosage units, each daily dosage unitcontaining said antiprogestin of the formula at a concentration of from2 to 50 mg; and ethinyl estradiol at a concentration of from about 10 toabout 35 μg; and c) optionally, a third phase of 4 daily dosage units ofan orally and pharmaceutically acceptable placebo.
 5. A pharmaceuticallyuseful kit adapted for daily oral administration which comprises: a) afirst phase of from 14 to 21 daily dosage units of a progestationalagent equal in progestational activity to about 35 to about 150 μglevonorgestrel; b) a second phase of from 1 to 11 daily dosage units ofan antiprogestin compound, each daily dosage unit containing anantiprogestin compound at a daily dosage of from about 2 to 50 mg;wherein said antiprogestin is of the formula:

 wherein: R₁ and R₂ are independently selected from the group consistingof H, alkyl, substituted alkyl, OH; O(alkyl), O(substituted alkyl), OAc,aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl,alkylheteroaryl, 1-propynyl, and 3-propynyl; or R₁ and R₂ are joined toform a ring comprising —CH₂(CH₂)_(n)CH₂—; —CH₂CH₂CMe₂CH₂CH₂—;—O(CH₂)_(m)CH₂—; O(CH₂)_(p)O—; —CH₂CH₂OCH₂CH₂—; —CH₂CH₂N(alkyl)CH₂CH₂—,or —CH₂CH₂NHCH₂CH₂—; n is an integer from 0 to 5; m is an integer from 1to 4; p is an integer from 1 to 4; or R₁ and R₂ together comprise adouble bond to ═C(CH₃)₂; ═C(C₃-C₆ cycloalkyl), ═O, or ═C(cycloether),wherein said cycloether is selected from the group consisting oftetrahydrofuranyl and hexahydropyranyl; R₃ is H, OH, NH₂, C₁ to C₆alkyl, substituted C₁ to C₆ alkyl, C₃ to C₆ alkenyl, alkynyl,substituted alkynyl, or COR^(A); R^(A) is H, C₁ to C₃ alkyl, substitutedC₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl; R₄is H, halogen, CN,NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy,substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, or substituted C₁ toC₆ aminoalkyl; R₅ is selected from the group consisting of (i), (ii),and (iii): (i) a substituted benzene ring of the formula:

X is selected from the group consisting of halogen, OH, CN, C₁ to C₃alkyl, substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ thioalkyl, substituted C₁ to C₃ thioalkyl, S(O)alkyl,S(O)₂alkyl, C₁ to C₃ aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂,C₁ to C₃ perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1to 3 heteroatoms, COR^(B), OCOR^(B), and NR^(C)COR^(B); R^(B) is H, C₁to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ toC₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, orsubstituted C₁ to C₃ aminoalkyl; R^(C) is H, C₁ to C₃ alkyl, orsubstituted C₁ to C₃ alkyl: Y and Z are independently selected from thegroup consisting of H, halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₄alkyl, and C₁ to C₃ thioalkyl; (ii) a five or six membered ring havingit its backbone 1, 2, or 3 heteroatoms selected from the groupconsisting of O, S, SO, SO₂ and NR_(6′) and containing one or twoindependent substituents selected from the group consisting of H,halogen, CN, NO₂ and C₁ to C₄ alkyl, C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, COR^(D), and NR^(E)COR^(D); R^(D) is H, C₁ to C₃ alkyl,substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy,substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, or substituted C₁ toC₃ aminoalkyl; R^(E) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃alkyl; R_(6′) is H, C₁ to C₃ alkyl, or C₁ to C₄ CO₂ alkyl; and c) athird phase of daily dosage units of an orally and pharmaceuticallyacceptable placebo; wherein the total number of the daily dosage unitsin the first phase, second phase and third phase equals
 28. 6. Apharmaceutically useful kit adapted for daily oral administration ofclaim 5 which comprises: a) a first phase of 21 daily dosage units of aprogestational agent equal in progestational activity to about 35 toabout 150 μg levonorgestrel; b) a second phase of 3 daily dosage unitsof said antiprogestin compound of formula I, each daily dosage unitcontaining an antiprogestin compound at a daily dosage of from about 2to 50 mg; and c) a third phase of 4 daily dosage units of an orally andpharmaceutically acceptable placebo.
 7. A pharmaceutically useful kitadapted for daily oral administration which comprises: a) a first phaseof from 18 to 21 daily dosage units of a progestostational agent equalin progestational activity to about 35 to about 150 μg levonorgestreland ethinyl estradiol at a daily dose range of from about 10 to about 35μg; and b) a second phase of from 1 to 7 daily dosage units of anantiprogestin at a daily dose of from about 2 to 50 mg; wherein saidantiprogestin is of the formula:

 wherein: R₁ and R₂ are independently selected from the group consistingof H, alkyl, substituted alkyl, OH; O(alkyl), O(substituted alkyl), OAc,aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl,alkylheteroaryl, 1-propynyl, and 3-propynyl; or R₁ and R₂ are joined toform a ring comprising —CH₂(CH₂)_(n)CH₂—; —CH₂CH₂CMe₂CH₂CH₂—;—O(CH₂)_(m)CH₂—; O(CH₂)_(p)O—; —CH₂CH₂OCH₂CH₂—; —CH₂CH₂N(alkyl)CH₂CH₂—,or —CH₂CH₂NHCH₂CH₂—; n is an integer from 0 to 5; m is an integer from 1to 4; p is an integer from 1 to 4; or R₁ and R₂ together comprise adouble bond to ═C(CH₃)₂; ═C(C₃-C₆ cycloalkyl), ═O, or ═C(cycloether),wherein said cycloether is selected from the group consisting oftetrahydrofuranyl and hexahydropyranyl; R₃ is H, OH, NH₂, C₁ to C₆alkyl, substituted C₁ to C₆ alkyl, C₃ to C₆ alkenyl, alkynyl,substituted alkynyl, or COR^(A); R^(A) is H, C₁ to C₃ alkyl, substitutedC₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl; R⁴ is H, halogen, CN,NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy,substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, or substituted C₁ toC₆ aminoalkyl; R₅ is selected from the group consisting of (i), (ii),and (iii): (i) a substituted benzene ring of the formula:

X is selected from the group consisting of halogen, OH, CN, C₁ to C₃alkyl, substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ thioalkyl, substituted C₁ to C₃ thioalkyl, S(O)alkyl,S(O)₂alkyl, C₁ to C₃ aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂,C₁ to C₃ perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1to 3 heteroatoms, COR^(B), OCOR^(B), and NR^(C)COR^(B); R^(B) is H, C₁to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ toC₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, orsubstituted C₁ to C₃ aminoalkyl; R^(C) is H, C₁ to C₃ alkyl, orsubstituted C₁ to C₃ alkyl: Y and Z are independently selected from thegroup consisting of H, halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₄alkyl, and C₁ to C₃ thioalkyl; (ii) a five or six membered ring havingit its backbone 1, 2, or 3 heteroatoms selected from the groupconsisting of O, S, SO, SO₂ and NR_(6′) and containing one or twoindependent substituents selected from the group consisting of H,halogen, CN, NO₂ and C₁ to C₄ alkyl, C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, COR^(D), and NR^(E)COR^(D); R^(D) is H, C₁ to C₃ alkyl,substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy,substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, or substituted C₁ toC₃ aminoalkyl; R^(E) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃alkyl; R_(6′) is H, C₁ to C₃ alkyl, or C₁ to C₄ CO₂ alkyl; and c) athird phase of from 0 to 9 daily dosage units of an orally andpharmaceutically acceptable placebo; wherein the total number of thedaily dosage units in the first phase, second phase and third phaseequals
 28. 8. A pharmaceutically useful kit adapted for daily oraladministration of claim 7 which comprises: a) a first phase of 21 dailydosage units of a progestostational agent equal in progestationalactivity to about 35 to about 150 μg levonorgestrel and ethinylestradiol at a daily dose range of from about 10 to about 35 μg; and b)a second phase of three daily dosage units of said antiprogestin offormula I administered at a daily dose of from about 2 to 50 mg; and c)a third phase of 4 daily dosage units of an orally and pharmaceuticallyacceptable placebo.
 9. A pharmaceutically useful kit adapted for dailyoral administration which comprises: a) a first phase of from 18 to 21daily dosage units, each daily dosage unit comprising a progestationalagent at a daily dose equal in progestational activity to from about 35to about 150 μg levonorgestrel and ethinyl estradiol at a daily doserange of from about 10 to about 35 μg b) a second phase of from 1 to 7daily dosage units, each daily dosage unit containing an antiprogestinat a concentration of from 2 to 50 mg; and ethinyl estradiol at aconcentration of from about 10 to about 35 μg; wherein saidantiprogestin is of the formula:

 wherein: R₁ and R₂ are independently selected from the group consistingof H, alkyl, substituted alkyl, OH; O(alkyl), O(substituted alkyl), OAc,aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl,alkylheteroaryl, 1-propynyl, and 3-propynyl; or R₁ and R₂ are joined toform a ring comprising —CH₂(CH₂)_(n)CH₂—; —CH₂CH₂CMe₂CH₂CH₂—;—O(CH₂)_(m)CH₂—; O(CH₂)_(p)O—; —CH₂CH₂OCH₂CH₂—; —CH₂CH₂N(alkyl)CH₂CH₂—,or —CH₂CH₂NHCH₂CH₂—; n is an integer from 0 to 5; m is an integer from 1to 4; p is an integer from 1 to 4; or R₁ and R₂ together comprise adouble bond to ═C(CH₃)₂; ═C(C₃-C₆ cycloalkyl), ═O, or ═C(cycloether),wherein said cycloether is selected from the group consisting oftetrahydrofuranyl and hexahydropyranyl; R₃ is H, OH, NH₂, C₁ to C₆alkyl, substituted C₁ to C₆ alkyl, C₃ to C₆ alkenyl, alkynyl,substituted alkynyl, or COR^(A); R^(A) is H, C₁ to C₃ alkyl, substitutedC₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl; R₄ is H, halogen, CN,NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy,substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, or substituted C₁ toC₆ aminoalkyl; R₅ is selected from the group consisting of (i), (ii),and (iii): (i) a substituted benzene ring of the formula:

X is selected from the group consisting of halogen, OH, CN, C₁ to C₃alkyl, substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ thioalkyl, substituted C₁ to C₃ thioalkyl, S(O)alkyl,S(O)₂alkyl, C₁ to C₃ aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂,C₁ to C₃ perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1to 3 heteroatoms, COR^(B), OCOR^(B), and NR^(C)COR^(B); R^(B) is H, C₁to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ toC₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, orsubstituted C₁ to C₃ aminoalkyl; R^(C) is H, C₁ to C₃ alkyl, orsubstituted C₁ to C₃ alkyl: Y and Z are independently selected from thegroup consisting of H, halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₄alkyl, and C₁ to C₃ thioalkyl; (ii) a five or six membered ring havingit its backbone 1, 2, or 3 heteroatoms selected from the groupconsisting of O, S, SO, SO₂ and NR_(6′) and containing one or twoindependent substituents selected from the group consisting of H,halogen, CN, NO₂ and C₁ to C₄ alkyl, C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, COR^(D), and NR^(E)COR^(D); R^(D) is H, C₁ to C₃ alkyl,substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy,substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, or substituted C₁ toC₃ aminoalkyl; R^(E) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃alkyl; R_(6′) is H, C₁ to C₃ alkyl, or C₁ to C₄ CO₂ alkyl; and c) athird phase of from 0 to 9 daily dosage units of an orally andpharmaceutically acceptable placebo; wherein the total number of thedaily dosage units in the first phase, second phase and third phaseequals
 28. 10. A pharmaceutically useful kit adapted for daily oraladministration of claim 9 which comprises: a) a first phase of 21 dailydosage units, each containing a progestational agent of this inventionat a daily dose equal in progestational activity to about 35 to about150 μg levonorgestrel and ethinyl estradiol at a daily dose range offrom about 10 to about 35 μg b) a second phase of 3 daily dosage units,each daily dosage unit containing said antiprogestin of formula I at aconcentration of from 2 to 50 mg; and ethinyl estradiol at aconcentration of from about 10 to about 35 μg; and c) a third phase of 4daily dosage units of an orally and pharmaceutically acceptable placebo.